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The Molecular Perspective: Bcl-2 and Apoptosis

Correspondence: David S. Goodsell, Ph.D., Associate Professor, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu Website: http://www.scripps.edu/pub/goodsell

	LEARNING OBJECTIVE

Top Learning Objective Further Reading

 
After completing this course, the reader will be able to:

1. Gain a basic understanding of the structure and function of the bcl-2 family of proteins, and their place in apoptosis and cancer.
   

Animals enforce a strict capital punishment on their cells. If any cell steps out of line, it is cleanly and promptly destroyed through the process of apoptosis. Candidates for apoptosis include cells that may be a danger to the organism, such as cells with damaged DNA or cells growing at improper rates. Apoptosis, however, is not restricted to rogue cells. It is also widely applied to normal cells that have simply become obsolete as organisms grow and develop.

Of course, there must be checks and balances on this powerful system. In cells, apoptosis is controlled through a tribunal of proteins, together known as the Bcl-2 family of proteins. Together, they weigh the pros and cons of cell death at any given time. Some of these proteins are pro-survival, arguing that the cell is healthy and useful. They normally dominate, and the cell continues living and performing its daily duties. Other proteins are pro-apoptotic, arguing for cell death. If they come to dominate, the mechanisms of apoptosis are activated and the cell destroys itself.

Cancer cells, in order to survive, must fool this watchdog system, continuing growth even when given death signals. In some cases, a mutation somewhere in the Bcl-2 system allows cancer cells to circumvent apoptosis. For instance, most follicular B-cell lymphomas contain a chromosomal translocation that moves the gene for Bcl-2 from its normal location to a position within the genes for immunoglobulins. In this new location, higher quantities of Bcl-2 are produced. Since Bcl-2 is a potent pro-survival advocate, it then shields the cancer cells from apoptotic instructions.

Over a dozen Bcl-2 family proteins have been discovered. About half, such as the BID protein shown in Figure 1, are pro-apoptotic. Like digestive enzymes or the enzymes involved in blood clotting, BID is activated by cleavage, releasing a fragment that initiates apoptosis. The story is not that simple, however, because these proteins also contain a control site, termed the "BH3" helix (for "Bcl-2 Homology"). The pro-survival proteins, such as Bcl-x_L shown in Figure 2, have a groove that binds tightly to this helix, blocking the apoptotic action. The balance of interactions, with pro-apoptotic proteins trying to deliver the message and pro-survival proteins blocking delivery, ultimately determines the fate of the cell.

View larger version (36K): [in this window] [in a new window]   Figure 1. The BID protein carries a pro-apoptotic signal. It is a small protein with a long flexible loop. Normally, it is found in a harmless form in the cytoplasm. When a death signal is received by the cell, a caspase makes a cut in the flexible loop (at the arrow), removing a large segment (colored yellow-green). This exposes a carbon-rich patch on the surface of the protein, allowing it to interact with proteins on the surface of mitochondria. Ultimately, this association disrupts the mitochondrion, triggering the large-scale mechanisms of apoptosis. The small blue segment of BID (the BH3 helix) interacts with pro-survival proteins, as shown in Figure 2.

View larger version (58K): [in this window] [in a new window]   Figure 2. The Bcl-xL protein, shown in red, carries a pro-survival signal. It has a groove that binds to the surface of pro-apoptotic proteins, such as BID, blocking the pro-apoptotic signal. Atomic coordinates were taken from entries 1ddb and 1bxl at the Protein Data Bank (http://www.pdb.org).

	FURTHER READING

Top Learning Objective Further Reading

 

Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 1998:281;1322–1326.[Abstract/Free Full Text]

Kelekar A, Thompson CB. Bcl-2-family proteins: the role of the BH3 domain in apoptosis. Trends Cell Biol 1998:8;324–330.[CrossRef][Medline]

Reed JC. Bcl-2 family proteins. Oncogene 1998:17;3225–3236.[CrossRef][Medline]

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